The incidence of thyroid cancer is increasing, with a global estimate of one-half million new cases this year. Thyroid carcinoma is usually first suspected by a physician when a solitary nodule is palpated on physical exam. Thyroid nodules, however, can be the result of a wide spectrum of causes, and a major concern is to accurately differentiate between benign and malignant nodules.
Cytology of a fine-needle aspiration (FNA) biopsy is the most widely used and cost-effective pre-operative test for initial thyroid nodule diagnosis (1). When FNA findings are diagnostic of papillary thyroid carcinoma, the specificity for malignancy approaches 95% (2). A common problem in clinical practice, however, is evaluation and management of thyroid tumors with a follicular pattern. FNA cytology cannot differentiate between follicular thyroid adenoma (FTA) and follicular thyroid carcinoma (FTC). Since cytology cannot distinguish between FTA and FTC they are often grouped together as indeterminate or follicular-patterned thyroid lesions. Surgical biopsy is needed to confirm FTA or FTC. Invasion through the tumor capsule or the blood vessels is an indicator of FTC. To provide an accurate diagnosis, most guidelines recommend surgical removal of a nodule diagnosed as having a follicular pattern. Complete thyroid resection and subsequent radioiodine therapy is indicated for those patients who ultimately have findings indicating carcinoma. Overall, only 8%-17% of these cytologically suspicious nodules are indeed malignant on histological examination (3).
Several genes have been reported to be associated with thyroid tumors. LGALS3 expression was proposed as a potential marker for pre-operative diagnosis of thyroid carcinoma (4-6). Subsequent findings, however, showed LGALS3 expression in benign lesions such as multinodular goiter and FTA (7,8). Recently, a chromosomal translocation t(2;3)(q13;p25) was reported in five of eight cases with FTC, but not in twenty cases with FTA (9). The authors suggested that the resulting PAX8/PPARG fusion gene could be useful in the diagnosis and treatment of thyroid cancer (9). This rearrangement, however, was found in 13%-30% of follicular adenomas (10-12). In addition, several molecular markers have been analyzed for their ability to discriminate between benign and malignant follicular tumors. The molecular markers include TPO, TP53, telomerase, and HMBE-1. Nonetheless, these candidate markers have not proved to have practical value for FNA pre-operative diagnosis of FTC (13-15). More recently cDNA array technology has been used to identify potentially important thyroid cancer-associated genes (16). Although many of the gene or gene patterns expressed in thyroid tumors have been described, the clinical problem of distinguishing FTC from FTA remains.
A large percentage of patients would, therefore, benefit greatly from improved diagnosis of FNA material. Improved diagnosis could reduce the number of surgeries, long-term health costs and post surgical complications. In particular, in many areas of the world where health care systems are over-burdened, limited resources for surgery could be directed more rapidly towards those with the highest risk of having carcinoma. Accurate molecular markers based on differential gene expression between FTA and FTC would be one means of improving the accuracy of diagnoses made from FNA.